Although the oxidation
(bleaching) of carotenoids has long been recognized as a property of soy bean
meal, the concept of a lipoxygenase activity was proposed in 1932 when André
E et al. suggest the presence of a lipid oxidase in the soya beans (André
E et al., C R Acad Sci Paris 1932, 194, 645). Four years later, it
was demonstrated, using the Warburg technique for measuring gas exchanges, that
proteins present in Lupinus albus seeds were also able to oxidized a
variety of fats (Craig FN, J Biol Chem 1936, 114, 727). More precisely,
a "carotene oxidase" was shown to be present in aqueous extracts of
soy beans, its action being dependant upon the presence of unsaturated fats
or fatty acids (Sumner JB et al., Enzymologia 1939, 7, 130). Soon
after, it was shown that unsaturated fats increased their peroxide number in
the presence of soy bean meal (Sumner JB et al., J Biol Chem 1940, 134, 531).

Hydroperoxides : Various lipoxygenases in plants and
animals produce several hydroperoxides (hydroperoxy eicosatetraenoic acids or
HpETE) from C18 and C20-fatty
acids (mainly arachidonic acid).
These regio-specific enzymatic reactions between oxygen and polyunsaturated
fatty acids formed new compounds, named oxylipins, which are most frequently
with the S-configuration (5-HpETE, 12-HpETE or 15-HpETE). The plant C18 fatty
acids, linoleic acid and linolenic acid, can be converted by the enzymes
a-dioxygenase,
9- or 13-lipoxygenase, giving rise to a multitude of oxylipins. These compounds
are involved in stress responses. Some oxylipins have direct antimicrobial properties,
whereas others may act as regulators of plant defense. Thus, methyl jasmonate
was directly proved to be essential for plant defense against the fungal root
pathogen Pythium mastophorum in Arabidopsis (Vijayan
P et al., Proc Natl Acad Sci 1998, 95, 7209).

An essential structural element of the C20-fatty acid for the enzymatic insertion
of molecular oxygen is the 1,4-pentadiene with the concomitant rearrangement
of the double bond to form a 1,3-conjugated diene which absorbs strongly around
236 nm.

These HpETE are formed in a variety of tissues and may undergo reactions dependent upon
the HpETE concerned. These reactions lead to hydroxy products (HETE) via reduction by
glutathion peroxidases, leukotrienes (LT) via isomerisation and dehydration,
prostaglandins (PG), dihydroperoxy compounds (DiHpETE) and lipoxines (Lx) by
isomerisation. HpETE are central intermediates but they also possess their own biological
activities.The different HpETE formed are reduced into their corresponding
stereospecific hydroxy products. They can also be formed via cytochrome P450. The 5-, 12-
and 15-HETE are the main forms but others have been detected (8-, 9-, 11-, 15-, 17-, 18-,
19- and 20-HETE, the 16- to 20-HETE being formed via cytochrome P450).

Furthermore, 12-HETE
may be transformed into more potent molecules, e.g. 10,11-dihydro-12-HETE.
The HETE are found in many types of cells from invertebrates to humans. They
are formed in vessels, epithelia, neuroglia, and germ cells. It was also found
that they are able to be incorporated into membrane phospholipids. It has been
observed that ionophore-stimulated monocytes generate 15-HETE attached to membrane
phosphatidylethanolamine (Maskrey BH et al., J Biol Chem 2000, 275, 33744).
It has been also found that, in response to thrombin, human platelets formed
12S-HETE which is partially esterified to phosphatidylethanolamine and phosphatidylcholine,
the major part remaining in a free state (Thomas CP et al., J Biol Chem 2010,
285, 6891). The observation of a preferential migration of these HETE-esterified
phosphatidylethanolamine suggests a role for these novel lipids in promoting
coagulation.
The first monocarbocyclic cyclopropyl-containing oxylipin from a marine organism
came as a result of studies on the mechanism of prostaglandin biosynthesis from
arachidonic acid by the Caribbean gorgonian Plexaura homomalla (Baertschi
SW et al., J Am Chem Soc 1989, 111, 500).

Cyclopropyl oxylipin

As source of oxylipins, linoleic
acid (18:2n-6) can be transformed into 9- and 13-derivatives (HODE, hydroxy-octadecadienoic
acids). A mushroom, Agaricus bisporus, was shown to be able to form also
two new linoleic acid derivatives, 8-hydroxy- and 8,11-dihydroxy-9,12-octadecadienoic
acids (Wadman MW et al., Lipids 2005, 40, 1163). g-linolenic
acid 18:3(n-6) can be transformed into 13-HOTrE (13-hydroxy-6,9,11-octadecatrienoic),
a-linolenic
acid 18:3(n-3) into 13-HOTrE (13-hydroxy-9,11,15-octadecatrienoic acid), 20:2(n-6)
into 11- and 15-derivatives (HEDE, hydroxy-eicosadienoic acids), 20:3(n-6) into
5-, 8-, 12- and 15-derivatives (HETrE), 20:3(n-9) or Mead acid into 5-HETrE
(5-hydroxy-6,8,11-eicosatrienoic acid) and 20:5(n-3) (EPA) into 5-, 8-, 9-,
11-, 12- and 15-derivatives (HEPE, hydroxy-eicosapentaenoic acids). Even docosahexaenoic
acid (22:6n-3) has been shown to be metabolized in the retina to a lipoxygenase
reaction product 11-hydroxy-4,7,9-t13,16,19-docosahexaenoic acid (Bazan NG
et al., Biochem Biophys Res Comm 1984, 125, 741).
The sequential action of 9-lipoxygenase and divinyl ether synthase on linoleic
or linolenic acid produces divinyl ether fatty
acids in plant which may be involved in the defense of plants against
attacking pathogens.
The separation of hydroxy fatty acids is performed by HPLC and their quantification is
performed by UV spectrophotometry using the absorbance of the conjugated diene (234-237nm,
e
around 23,000).

Leukotrienes
: The 5-lipoxygenase
has received great attention since it initiates the formation of leukotrienes.
First, oxygen is inserted at carbon 5 to produce an unstable compound (LTA4).
This compound is converted either to LTB4 by a hydrolase or to LTC4 by a combination
with a glutathion residue. Further, by cleavage of one L-glutamic acid, LTD4
is formed which may be again converted into LTE4 after removal of one L-glycine
residue. LTC4, LTD4 and LTE4 are known as cysteinyl leukotrienes.
They substances are considered as local hormones formed when necessary in response
to cell specific hormonal, chemical or immunological stimuli. They are thought
to be the mediators of bronchial asthma and allergic diseases. LTD4 has potent
chemostatic activities and may have important roles in inflammatory process.

Polyhydroxy fatty acids : It has been reported dozens
of polyhydroxy fatty acids produced by multiple lipoxygenation reactions of
arachidonic acid. For example, 5,12-DiHETE is formed in leukocytes by double
oxygenation of 20:4(n-6) via 5- and 12-lipoxygenases. This molecule is not biosynthetically
related to LTB4, although it bears hydroxyl groups at C5 and C12. It has an
opposite configuration at C12 and another conjugated triene configuration. DiHETE
may be formed by 5-, 6-, 8-, 12-, 14-, 15-, 19-, and 20-lipoxygenases. To complicate
the pathways, some, as 5,6- or 5,12-DiHETE, were shown to be formed also by
nonenzymatic hydrolysis of LTB4 or LTA4, respectively. They are produced in
leukocytes, eosinophiles or platelets. They are generally related with muscle
contraction, cell degranulation, superoxide production and chemotactism. They
are detected and quantified owing to their strong UV absorption (conjugated
triene) at about 270nm (e: 30,000-50,000). Some of the best known DiHETE are
depicted below.

Some docosatrienes
(docosanoids) are acyclic lipoxygenase metabolites of 22-carbon atom polyunsaturated
fatty acids (DHA) containing a conjugated triene with two secondary allylic
alcohols. The two main metabolites are protectin D1 and its regioisomer maresin
1, they are involved in the resolution and more specifically the termination
of the inflammation process.

Lipoxins
(LX) : they may be also formed from several polyhydroxy fatty acids. They contain
a conjugated tetraene structure responsible for their strong absorbance at 300
nm (e= 50,000). They can be formed through several metabolic pathways including
a combination of 5-, 12- or 15-lipoxygenases, peroxidase, dehydrase and hydrolase.
LXA4 (5, 6, 15-trihydroxy) and LXB4 (5, 14, 15-trihydroxy) are the major lipoxins
which display original activity profiles. Thus, they stimulate lipid remodeling
in neutrophiles, contraction of lung muscle, protein kinase C activation, inhibition
of inositol P3 production or microvascular bed dilation.

Hepoxilins : A new bioactive group of hydroxy and
epoxy fatty acids has been identified after incubation of blood platelets with
arachidonic acid (Walker IC et al., Prostaglandins 1979, 18, 173). These
derivatives were named hepoxilin. Several types were described, epoxy
arachidonic acid being either mono- or tri-hydroxylated. Hepoxilin A3 is shown
below.

Jasmonate was found in 1962 in Jasminum
oil (Demole E et al., Helv Chim Acta 1962, 45, 675) and jasmonic acid was
isolated in 1971 in a fungus culture (Aldridge DC et al., J Chem Soc 1971, C,
1623). Subsequently, both of these compounds, as well as a number of
homologues, have been shown to be widespread in the plant kingdom and in some
fungi. The most ancient and the only prokaryotic organism known to synthesize
jasmonic acid form linolenic acid is the cyanobacterium Spirulina (Ueda
J et al., Bull Univ Osaka Prefect Ser B 1991, 23, 103). It is noteworthy
that cyanobacteria are believed to have given rise to some eukaryotic
chloroplasts. Except these organisms, jasmonic acid occurs ubiquitously in
organisms that have plastids. Jasmonic acid has been reported as constituent of
the Black Sea red alga, Gelidium latifolium (Krupina MV et al., Z
Naturforsch 1991, 46C, 1127).
Jasmonate is structurally related to cis-jasmone
(same but without the carboxyl group), all are cyclopentyl
fatty acid derivatives, both being fragrant components of
essential oils of jasmine
(methyl jasmonate makes up some 2-3% of jasmin oil). Jasmone was the first
component of the jasmonate family discovered in jasmine flower oil (Hesse A et
al., Chem Ber 1899, 32, 2611) but its structure was determined forty years later
(Ruzicka L et al., Helv Chim Acta 1933, 16, 1208).

cis-Jasmone

Jasmone
is a product of the catabolism of jasmonic acid (Koch T et al., Helv Chim
Acta 1997, 80, 838) and is well known as a component of plant volatiles (jasmin,
jonquil, peppermint oil, tea flavor),
its release being induced
by damage during insect herbivory. It was found to be electrophysiologically
active and also to be repellent in laboratory and field studies (Birkett
MA et al., PNAS 2000, 97, 9329). Furthermore, jasmone induced the
production of volatile compounds, including the monoterpene ocimene, which
affect plant defense, for example by stimulating the activity of parasitic
insects.
Jasmonate synthetic pathway
from linolenic acid was first proposed in 1983 (Vick
BA et al., Biochem Biophys Res Commun 1983, 111, 470). Jasmonate
is
synthesized via several key enzymes including lipoxygenase, allene oxide
synthase, and allene oxide cyclase (octadecanoic pathway). It can be conjugated
to amino acids, i.e. leucine, valine, isoleucine (Staswick
PE et al., Plant cell 2004, 16, 2117), tryptophane and
b-glucoside.
Octadecanoids are now considered mainly as wound-inducible compounds elicited by
herbivorous attack and are proposed to act as cellular messengers during defense
responses (Farmer
EE et al., Plant cell 1992, 4, 129; Fliegmann J et al., Biol Chem 2003, 384, 437).
Methyl jasmonate vapor is a powerful signal for the induction of proteinase
inhibitor gene expression in the leaves of wounded plants but also of nearby
plants, the first precise
role attributed to this oxylipin (Farmer
EE et al., Proc Natl Acad Sci USA 1990, 87, 7713). These data suggest
that volatile methyl jasmonate may play physiological roles (Farmer EE et
al., Plant Physiol 1992, 98, 995). Furthermore, the use of jasmonate as a
spray has been investigated in a number of systems for the protection of plants
from pests and pathogens. Several investigations have shown that jasmonic acid,
apart its signaling effect in plants, may also act as a signal in fungi.
Another compound of the jasmonate family, dinor-oxo-phytodienoic acid, has been
described in leaves of Arabidopsis and potato (Weber
H et al., PNAS 1997, 94, 10473). It differs from jasmonic acid in being
formed from a C16 fatty acid (16:3n-3).
It has been shown that a precursor of jasmonic acid, 12-oxophytodienoic acid, is
esterified in the sn-1 position of plastid-specific galactolipids (MGDG) and
released during wounding experiments. This compound is subsequently transformed
into jasmonic acid, the true mediator of plant herbivore defense (Stelmach BA
et al., J Biol Chem 2001, 276, 12832).

12-oxophytodienoic acid

A review of the various aspects of jasmonate signaling has been reviewed (Plant
hormones, Litwack G Ed, Elsevier, 2005; Katsir L et al., Curr Opin Plant Biol
2008, 11, 428). The specific role of jasmonates in plant responses to
pathogenesis and herbivory attack has been reviewed (Farmer EE et al., Curr
Opin Plant Biol 2003, 6, 372).
A scheme of jasmonate biochemical pathway may be consulted at science
signaling web site
or downloaded from here.

The monoglycoside derivative of
tuberonic acid was shown to be the natural substance which had a potent
tuber-inducing activity in the leaves of potato at a concentration of 0.01
mg/l.
Methyl and ethyl derivatives of
tuberonic acid glycoside were described in Jerusalem artichoke and Salvia
officinalis, respectively. This substance is synthesized from epi-jasmonic acid in the leaves and transported down to stolons. The
b-glucoside of
tuberonic acid is more active than the free acid and suggests that conjugated
fatty acid metabolites may play an important role as natural plant regulators (Farmer
EE, Plant Mol Biol 1994, 26, 1423).

Cucurbic acid is a jasmonic acid analogue with 12 carbon atoms and a
hydroxylated cyclopentane cycle which has similar properties as jasmonic acid.

Cucurbic acid

An extensive review on the various jasmonates, their activities and metabolism
has been released by Beale MH et al (Nat Prod Rep 1998, 15, 533).

Bacillariolides : Novel eicosanoids have been
isolated from the wild and cultured cells of the diatom, Pseudo-nitzschia
multiseries, a causative organism of so-called amnesic shellfish poisoning (Wang
R et al., J Chem Soc, Chem Commun 1990, 413). Two arachidonic acid
derivatives found in the cells have cyclopentane and lactone rings. One of them
is shown below.

Bacillariolide I

Bacillariolide I is known to possess
significant inhibitory activity against phospholipase A2 and is not at the
origin of Pseudo-nitzschia toxicity (Shimizu Y, Annu
Rev Microbiol 1996, 50, 431). It was shown that the same diatom
excretes in the culture medium a C12 metabolite (bacillariolide III, side chain
of 5 carbon atoms) which is likely formed by the cleavage of bacillariolide I (Zheng
N et al., Chem Commun 1997, 399).